rs757435431

Positions:

• chr9-114504718-CCCG-C
• chr9-114504718-CCCG-CCCGCCG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP3 BS1_Supporting

The NM_015404.4(WHRN):​c.81_83del​(p.Gly29del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,511,078 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: WHRN NM_015404.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.11

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_015404.4
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000204 (31/152270) while in subpopulation AFR AF= 0.000698 (29/41576). AF 95% confidence interval is 0.000498. There are 1 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WHRN	NM_015404.4	c.81_83del	p.Gly29del	inframe_deletion	1/12	ENST00000362057.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WHRN	ENST00000362057.4	c.81_83del	p.Gly29del	inframe_deletion	1/12	1	NM_015404.4	P1
WHRN	ENST00000374057.3	c.81_83del	p.Gly29del	inframe_deletion	1/2	2
WHRN	ENST00000673697.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152164 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 31 AN: 1358808 Hom.: 0 AF XY: 0.0000209 AC XY: 14 AN XY: 670216

Gnomad4 AFR exome AF: 0.000528

Gnomad4 AMR exome AF: 0.0000315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000400

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000187

Gnomad4 OTH exome AF: 0.000176

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152270 Hom.: 1 Cov.: 34 AF XY: 0.000215 AC XY: 16 AN XY: 74454

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This variant, c.81_83del, results in the deletion of 1 amino acid(s) of the WHRN protein (p.Gly29del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 228565). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 19, 2017	The p.Gly28del variant (rs757435431) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 228565). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.008% (identified in 11 out of 132,060 chromosomes). The p.Gly28del variant is an in-frame contraction of a poly-glycine repeat and is in a region not conserved among species, suggesting this deleted amino acid is not critical for WHRN protein structure/function. However, based on the available information, the clinical significance of the p.Gly28del variant cannot be determined with certainty. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 17, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Gly29del vari ant in DFNB31 has been previously reported in 1 individual with hearing loss by our laboratory; however, a variant affecting the remaining copy of DFNB31 was no t identified. This variant has been identified in 1/356 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 757435431); however, this frequency is not high enough to rule out a pathogenic role. The glycine (Gly) residue at position 29 lies in a poly-glycine tract with in the DFNB31 protein, and this variant is predicted to result in an in-frame de letion of a single glycine residue (Gly) within this poly-glycine tract. The reg ion encompassing this poly-glycine tract is not well conserved across species an d several species have an in-frame glycine deletion at this position or nearby g lycine positions, suggesting the variant may not impact the protein. However, th is information is insufficient to rule out pathogenicity. In summary, while the clinical significance of the p.Gly29del variant is uncertain, the conservation d ata suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757435431; hg19: chr9-117266998;